Genetics and diagnosing spinal muscular atrophy (SMA)

SMA is a hereditary disease with a well-characterised genetic cause1-3

SMA is an autosomal recessive genetic disease in which an individual inherits two deleted or mutated SMN1
genes—one from each parent:4

Noncarriers of SMA have 2 copies of the SMN1 gene, one on each chromosome 5. Individuals are defined as carriers if they have genetic patterns which may include:5

1 copy of the SMN1 gene on one chromosome and 0 copies on the other

2 copies of the SMN1 gene on one chromosome and 0 copies on the other

Molecular genetic testing is an important tool in the diagnosis of SMA6,7

The SMN1 gene deletion test is recommended as the first diagnostic step for a patient suspected to have SMA. The deletion status can be tested by using polymerase chain reaction (PCR) to determine if both copies of SMN1 exon 7 are absent, which occurs in 95% of affected individuals. PCR can reliably and accurately measure SMN1 and SMN2 copy numbers over a wide range (i.e. 0–6 copies).5,8

If a patient is found to have a single copy of the SMN1 gene but the clinical presentation is suggestive of SMA, sequencing of the remaining SMN1 gene may identify the mutation and confirm the diagnosis of SMA.6

If the individual presenting with symptoms of SMA is shown to have 2 copies of the SMN1 gene, then other motor neuron disorders might be considered in the differential diagnosis.5

Although newborn screening is not yet standard practice, time to diagnosis is critical. Based on the natural history of the disease, earlier diagnosis leading to earlier intervention may help improve outcomes for individuals with SMA.10

Diagnostic delays are common in SMA

A systematic literature review of publications was conducted to assess the diagnostic delay in SMA. From a subset of 5 studies (including one Australian study) that reported both age of onset and age at confirmed diagnosis, the delay to diagnosis ranged from months to years.11

SMA phenotype

Age of onset

(weighted mean, SD)

Age at confirmed diagnosis

(weighted mean, SD)

Delay in diagnosis

(weighted mean, SD)

SMA phenotype

Type I

Age of onset (weighted mean, SD)

2.5 months(0.6) (n=420)

Age at confirmed diagnosis (weighted mean, SD)

6.3 months(2.2) (n=271)

Delay in diagnosis (weighted mean, SD)

3.6 months(1.9) (n=264)

SMA phenotype

Type II

Age of onset (weighted mean, SD)

8.3 months(1.6) (n=357)

Age at confirmed diagnosis (weighted mean, SD)

20.7 months(2.6) (n=219)

Delay in diagnosis (weighted mean, SD)

14.3 months(0.0) (n=105)

SMA phenotype

Type III

Age of onset (weighted mean, SD)

39.0 months(32.6) (n=63)

Age at confirmed diagnosis (weighted mean, SD)

50.3 months(12.9) (n=60)

Delay in diagnosis (weighted mean, SD)

43.6 months(0.0) (n=25)

SD= Standard deviation.

Number of studies used to determine weighted mean age of diagnosis was 4, 4, and 3 for Type I, II, and III SMA, respectively.11

Delays in diagnosis of SMA can result in missed opportunities for optimal early management and treatment initiation. It has been suggested that earlier interventions in SMA may be associated with better outcomes, as shown in other paediatric diseases.11

Differential diagnoses of SMA

Hypotonia in infants

Infants with hypotonia (“floppy babies”) often pose a diagnostic challenge for clinicians because hypotonia may be the presenting sign of both benign and serious conditions. Classic signs may be displayed by hypotonic infants, including:14,15

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